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Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial.
Lancet HIV 2015; 2(11):e464-73LH

Abstract

BACKGROUND

Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen.

METHODS

Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per μL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants.

FINDINGS

Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group).

INTERPRETATION

A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide.

FUNDING

The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories.

Authors+Show Affiliations

Department of Internal Medicine, Hospital Universitario La Paz, Idipaz, Madrid, Spain. Electronic address: jose.bernardino@salud.madrid.org.University College London, London, UK.School of Medicine, University College Dublin, Dublin, Ireland.University Bordeaux, ISPED, Centre Inserm U897-Epidemiologie-Biostatistique, Bordeaux, France.Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.Medical Research Council Clinical Trials Unit at University College London, London, UK.Department of Global Health and Division of Infectious Diseases, Academic Medical Centre, Amsterdam, Netherlands.Hospital Pitie-Salpetriere UPMC University Paris 06, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.Saint Pierre University Hospital Brussels, Brussels, Belgium.University Bordeaux, ISPED, Centre Inserm U897-Epidemiologie-Biostatistique, Bordeaux, France.Medical Research Council Clinical Trials Unit at University College London, London, UK.Laboratory Medicine Department, Hospital Universitario La Paz, Madrid, Spain.Vita-Salute San Raffaele Scientific Institute, Milan, Italy.Department of Infectious and Tropical Diseases, Hôpital Saint-Antoine, AP-HP and INSERM UMR_S 1136, Paris, France.University Bordeaux, ISPED, Centre Inserm U897-Epidemiologie-Biostatistique, Bordeaux, France.College of Professors of Infectious and Tropical Diseases, Paris, France.Department of Internal Medicine, Hospital Universitario La Paz, Idipaz, Madrid, Spain.No affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26520926

Citation

Bernardino, Jose I., et al. "Bone Mineral Density and Inflammatory and Bone Biomarkers After Darunavir-ritonavir Combined With Either Raltegravir or Tenofovir-emtricitabine in Antiretroviral-naive Adults With HIV-1: a Substudy of the NEAT001/ANRS143 Randomised Trial." The Lancet. HIV, vol. 2, no. 11, 2015, pp. e464-73.
Bernardino JI, Mocroft A, Mallon PW, et al. Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial. Lancet HIV. 2015;2(11):e464-73.
Bernardino, J. I., Mocroft, A., Mallon, P. W., Wallet, C., Gerstoft, J., Russell, C., ... Arribas, J. R. (2015). Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial. The Lancet. HIV, 2(11), pp. e464-73. doi:10.1016/S2352-3018(15)00181-2.
Bernardino JI, et al. Bone Mineral Density and Inflammatory and Bone Biomarkers After Darunavir-ritonavir Combined With Either Raltegravir or Tenofovir-emtricitabine in Antiretroviral-naive Adults With HIV-1: a Substudy of the NEAT001/ANRS143 Randomised Trial. Lancet HIV. 2015;2(11):e464-73. PubMed PMID: 26520926.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial. AU - Bernardino,Jose I, AU - Mocroft,Amanda, AU - Mallon,Patrick W, AU - Wallet,Cedrick, AU - Gerstoft,Jan, AU - Russell,Charlotte, AU - Reiss,Peter, AU - Katlama,Christine, AU - De Wit,Stephane, AU - Richert,Laura, AU - Babiker,Abdel, AU - Buño,Antonio, AU - Castagna,Antonella, AU - Girard,Pierre-Marie, AU - Chene,Genevieve, AU - Raffi,Francois, AU - Arribas,Jose R, AU - ,, Y1 - 2015/09/30/ PY - 2015/08/04/received PY - 2015/08/25/revised PY - 2015/08/25/accepted PY - 2015/11/2/entrez PY - 2015/11/2/pubmed PY - 2016/9/22/medline SP - e464 EP - 73 JF - The lancet. HIV JO - Lancet HIV VL - 2 IS - 11 N2 - BACKGROUND: Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen. METHODS: Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per μL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants. FINDINGS: Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group). INTERPRETATION: A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide. FUNDING: The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories. SN - 2352-3018 UR - https://www.unboundmedicine.com/medline/citation/26520926/Bone_mineral_density_and_inflammatory_and_bone_biomarkers_after_darunavir_ritonavir_combined_with_either_raltegravir_or_tenofovir_emtricitabine_in_antiretroviral_naive_adults_with_HIV_1:_a_substudy_of_the_NEAT001/ANRS143_randomised_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-3018(15)00181-2 DB - PRIME DP - Unbound Medicine ER -